PROJECT SUMMARY About 1 out of 7 individuals experience Major Depressive Disorder (MDD) during their life time but only 1 out of 3 achieve remission with current treatment. MDD is the 2nd largest source of disability and costs the economy $200 billion annually. MDD is a very heterogeneous disorder that affects how one processes events - ?what makes you feel good? (positive valence), ?what makes you feel bad? (negative valence), and how the brain processes body-relevant information (interoception). Some have proposed that inflammation plays a central role in a subset of depression that is characterized clinically by an increase in c-reactive protein (CRP). This proposal seeks to better understand the biological processes that underlie the inflammatory subtype of MDD by examining subgroups of depressed individuals with low CRP (?1mg/mL), and high CRP (?3mg/mL). In particular, an experimental manipulation of the immune system will be used to contrast the clinical, immune, and neural function of depressed subjects with high and low CRP. Specifically, the low CRP (n=44) and high CRP (n=44) groups will be divided to receive either endotoxin (0.8 ng/kg) or saline in order to induce a transient inflammatory response. Serial blood draws will be obtained during this time to quantify the pattern of inflammatory response using several inflammatory markers. At the same time, subjects will complete clinical ratings and undergo a pre- and post-endotoxin MRI scan to measure how the transient inflammatory response affects brain processing of anticipatory reward and interoception. For Phase 2 of this project, all subjects will undergo 10 weeks of behavioral therapy (BT) after they have completed the transient inflammatory perturbation and clinical outcomes will be measured. This project has two main goals (focused on year 1-3 and 4-5): (1) to delineate how the depressed people with and without inflammation differ in clinical, immune, and neural function both at baseline and under endotoxin, and (2) to test whether these changes are predictive of BT treatment outcome. The main hypotheses are that: (1) relative to the low CRP group, the high CRP group will show baseline (a) increases in anhedonic symptoms, (b) increases in IL-6 and TNF, (c) decreases in ventral striatal activity during positive valence processing, and (d) decreases in insular cortex activity during interoceptive processing as well as disproportionate changes in these phenotypic measures in the endotoxin vs. placebo condition. (2) The degree of these baseline differences and endotoxin-induced changes will predict: (a) changes in depression scores over the course of the BT and response and remission rates after BT. This research is innovative because it is the first inflammatory perturbation experiment in a group of depressed individuals. It is also highly impactful because we need to understand the mechanisms through which inflammation leads to depression in high CRP individuals in order to (1) facilitate the development of new pharmacological or behavioral therapies, and (2) identify predictive biomarkers.